Method for stable and controlled delivery of (-)-hydroxycitric acid

ABSTRACT

The present invention provides stable encapsulated (−)-hydroxycitric acid (“HCA”)-containing compositions and methods of making the same. A method is provided by which the hygroscopic salts of HCA in their relatively pure and active forms, including especially the potassium salt, but also including the sodium salt, are rendered non-hygroscopic and stable (that is, not prone to lactonization, not readily subject to attachment to ligands which inhibit absorption or lead to excretion, and so forth) such that these HCA salts might be included in dry delivery formats, liquid delivery and in controlled-release vehicles. The nonhygroscopic salts of HCA and its derivatives likewise may be protected against acid degradation, lactonization and undesirable ligand binding when exposed to acidic environments or other challenging conditions. The method taught herein can be employed to reduce the polar/ionic qualities of HCA salts and derivatives when presented to the intestinal lumen to provide advantages in absorption.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 10/447,992,filed May 29, 2003, the contents of which are hereby incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to stable microencapsulated/coated(−)-hydroxycitric acid compositions and methods of making the same.

BACKGROUND OF THE INVENTION

(−)-Hydroxycitric acid (HCA) is a naturally-occurring acid found in thefruit of members of the plant genus Garcinia. HCA can affect themetabolic functions of mammals, including humans. HCA, as well asseveral synthetic derivatives of citric acid, can inhibit the productionof fatty acids from carbohydrates, suppress appetite, and inhibit weightgain (Sullivan et al., American Journal of Clinical Nutrition 1977; 30:767). Numerous other benefits have been attributed to the use of HCA,including, but not limited to, an increase in the metabolism of fatstores for energy and an increase in thermogenesis (the metabolism ofenergy sources to produce body heat in an otherwise wasteful cycle).

Free HCA, calcium, magnesium and potassium salts of HCA (i.e.,hydroxycitrates, also referred to as HCA) and poorly characterizedmixtures of two or more of these minerals were sold in the Americanmarket. Calcium HCA and sodium HCA salts have been sold as early as1994. Most of the commercial preparations of HCA sold to date consist ofcalcium salts of varying degrees of purity or, more recently, poorlycharacterized mixtures of calcium HCA and potassium HCA salts.

Therapeutic use of HCA salts has been limited, however, by their poorabsorption and chemical Instability at acidic pH, e.g., inactivation ofHCA salts via lactonization upon exposure to the acidic milieu of themammalian gut. HCA is extremely hygroscopic, in both its preferred formas potassium HCA salt and in its secondarily preferred form as sodiumHCA salt. As such, HCA in its more biologically active forms can be onlybe maintained as a powder under controlled conditions.

Prior methods to manipulate HCA salts failed to accommodate itsinstability in acid and hygroscopic nature. Without special precautions,HCA, in its free acid form and in its potassium and sodium salt forms,will bind to numerous other compounds. The binding of HCA to othercompounds can affect its bioavailability to a subject, e.g., as a resultHCA is less assimilated by a subject.

Prior methods to formulate the preferred salts of HCA (i.e., potassiumHCA and sodium HCA) have been limited because they did not yield aformulation of HCA that was fully stable and workable as capsules,tablets, powders, in beverages or prepared snacks, or in controlledrelease vehicles. Accordingly, there remains a need for HCA-containingcompounds suitable for inclusion in dry delivery formats, liquiddelivery and in controlled-release vehicles.

BRIEF SUMMARY OF THE INVENTION

The present invention provide stable, non-hygroscopic HCA-containingcompounds (e.g., potassium HCA) useful for tableting,microencapsulation, the production of controlled-release vehicles andincorporation into dry powders. In one embodiment of the invention, theHCA-containing compound is formulated in a dry delivery system. The drydelivery systems include, e.g., a tablet; dry powder; and dry mealreplacement mixture. In another embodiment of the invention, theHCA-containing compound is formulated in a liquid delivery system. Theliquid delivery systems include (e.g., a capsule); caplet; and beverage.In yet another embodiment of the invention, the HCA-containing compoundis formulated in a controlled-release system. The controlled-releasesystem includes, e.g., a tablet; caplet; and capsule.

In one embodiment of the invention, the HCA-containing compounds of theinvention include HCA, one or moreabsorption-enhancer/controlled-release agents and one or morerate-controlling excipients. The HCA can include, e.g., HCA free acid;HCA salts; HCA derivatives; or any combination thereof. In oneembodiment of the invention, the HCA is present from about 1.0% to about80% of the total weight of the HCA-containing compound. In oneembodiment of the invention, the HCA is present from about 5% to about70% of the total weight of the HCA-containing compound. In oneembodiment of the invention, the HCA is present from about 10% to about60% of the total weight of the HCA-containing compound.

The absorption-enhancer/controlled-release agents can include, e.g.,d-alpha-tocopheryl polyethylene glycol succinate (TPGS); Lubritab®;volcanic oils; high viscosity grades of conjugated polyethylene glycol;ethylcellulose, carboxymethylcellulose, cellulose propionate; celluloseacetate propionate; cellulose acetate butyrate; cellulose acetatephthalate (CAP); cellulose triacetate; hydroxypropyl-methylcellulosephthalate; polymethyl methacrylate; polyethyl methacrylate; polybutylmethacrylate; polyisobutyl methacrylate; polyhexyl methacrylate;polylsodecyl methacrylate; polylauryl methacrylate; polyphenylmethacrylate; polymethyl acrylate; polyisopropyl acrylate; polyisobutylacrylate; polyoctadecyl acrylate; polyethylene; polyethylene lowdensity; polyethylene high density; polypropylene; polyethylene oxide;polyethylene terephthalate; polyvinyl isobutyl ether; polyvinyl acetate;polyvinyl acetate phthalate; polyvinyl chloride; polyurethane; othercopolymers of acrylic and methacrylic and esters; waxes; shellac; zein;hydrogenated vegetable oils; polyvinyl alcohol; polyvinylpyrrolidone;methyl cellulose; hydroxypropyl cellulose; hydroxpropylmethyl celluloseor polyethylene glycol; or a mixture thereof. In one embodiment of theinvention, the one or more absorption-enhancer/controlled-release agentsare present from about 1.0% to about 50% of the total weight of theHCA-containing compound. In one embodiment of the invention, the one ormore absorption-enhancer/controlled-release agents are present fromabout 1.0% to about 40% of the total weight of the HCA-containingcompound. In one embodiment of the invention, the one or moreabsorption-enhancer/controlled-release agents are present from about1.0% to about 30% of the total weight of the HCA-containing compound.

The rate-controlling excipients can include, e.g., Eastacryl; Kollicoat®IR (polyvinylalcohol-polyethyleneglycol graft-copolymer); celluloseacetate phthalate; Kollicoat® SR; ethyl cellulose; Eudragit® (family ofacrylate and methacrylate-based coatings); zein (vegetable protein);acrylic polymers; polyvinyl acetate phthalate; hydroxymethylpropylmethylcellulose phthalate; cellulose acetate trimalleate; acrylic polymerplasticizers; polymers of polylactic acid; polymers of glycolic acid,and mixtures thereof; Primogel; Pruv™ (stearyl fumarate sodium); citrateesters; triethyl citrate; propylene glycol; and dibutyl sebacate. In oneembodiment of the invention, the one or more rate-controlling excipientsare present from about 0.0001% to about 60% of the total weight of theHCA-containing compound. In one embodiment of the invention, the one ormore rate-controlling excipients are present from about 0.001% to about50% of the total weight of the HCA-containing compound. In oneembodiment of the invention, the one or more rate-controlling excipientsare present from about 0.01% to about 25% of the total weight of theHCA-containing compound.

In one embodiment of the invention, the chloride concentration of theHCA-containing compound is less than about 2.5% of the total weight ofthe HCA-containing compound. In one embodiment of the invention thechloride concentration of the HCA-containing compound is less than about1.0% of the total weight of the HCA-containing compound. In oneembodiment of the invention, the chloride concentration of theHCA-containing compound is less than about 0.5% of the total weight ofthe HCA-containing compound. In one embodiment of the invention, thetotal halogen content as chloride of the HCA-containing compound is lessthan about 2.9% of the total weight of the HCA-containing compound. Inone embodiment of the invention, the total halogen content as chlorideof the HCA-containing compound is less than about 1.0% of the totalweight of the HCA-containing compound. In one embodiment of theinvention, the total halogen content as chloride of the HCA-containingcompound is less than about 0.6% of the total weight of theHCA-containing compound.

In one aspect of the invention, the HCA-containing compound include HCA,one or more absorption-enhancer/controlled-release agents, one or morerate-controlling excipients, and one or more lubricants. The lubricantsinclude, e.g., magnesium stearate, calcium stearate; sodium stearate,glycerol monostearate; stearic acid; Lubritab®; hydrogenated vegetableoils; waxes; talc; boric acid; sodium benzoate; sodium acetate; sodiumchloride; DL-leucine; sodium oleate; sodium lauryl sulfate; magnesiumlauryl sulfate and polyethylene glycols and kaolin. In one embodiment ofthe invention, the one or more lubricants the are present from about0.0001% to about 10% of the total weight of the of the HCA-containingcompound. In one embodiment of the invention, the one or more lubricantsare present from about 0.001% to about 10% of the total weight of the ofthe HCA-containing compound. In one embodiment of the invention, the oneor more lubricants are present from about 0.01% to about 5% of the totalweight of the of the HCA-containing compound.

In one aspect of the invention, the HCA-containing compound include HCA,one or more absorption-enhancer/controlled-release agents, one or morerate-controlling excipients, and one or more bulking agents/binders. Thebulking agents/binders include, e.g., starch paste; acacia; sucrose;poly vinyl pyrrolidone (PVP); hydroxy proplyl methyl cellulose (HPMC);methyl cellulose; gelatin; potato starch; micro crystalline cellulose(MCC); pregelatinized starch (PGS); Primogel (Sodium starch glycolate,USP/NF, Ph. Eur.); Primellose (Crosscarmelose sodium, USP/NF, ph. Eur.);di-calcium phosphate and tri-calcium phosphate. In one embodiment of theinvention, the one or more bulking agents/binders are present from about0.01% to about 30% of the total weight of the of the HCA-containingcompound. In one embodiment of the invention, the one or more bulkingagents/binders are present from about 0.1% to about 30% of the totalweight of the of the HCA-containing compound. In one embodiment of theinvention, the one or more bulking agents/binders are present from about0.1% to about 25% of the total weight of the of the HCA-containingcompound.

In one aspect of the invention, the HCA-containing compounds includeHCA, one or more absorption-enhancer/controlled-release agents, one ormore rate-controlling excipients, one or more lubricants, and one ormore bulking agents/binders.

In one aspect of the invention, the HCA-containing compounds in include,HCA and one or more rate-controlling excipients. In one embodiment ofthe invention the HCA is present from about 1.0% to about 80% of thetotal weight of the HCA-containing compound. In one embodiment of theinvention, the HCA is present from about 5% to about 70% of the totalweight of the HCA-containing compound. In one embodiment of theinvention, the HCA is present from about 10% to about 60% of the totalweight of the HCA-containing compound. In one embodiment of theinvention, the one or more rate-controlling excipients are present fromabout 0.0001% to about 60% of the total weight of the HCA-containingcompound. In one embodiment of the invention, the one or morerate-controlling excipients are present from about 0.001% to about 50%of the total weight of the HCA-containing compound. In one embodiment ofthe invention, the one or more rate-controlling excipients are presentfrom about 0.01% to about 25% of the total weight of the(−)-hydroxycitrate-containing compound.

In one aspect of the invention, the HCA-containing compounds in include,HCA and one or more lubricants. In one embodiment of the invention, theHCA is present from about 50% to about 99% of the total weight of theHCA-containing compound. In one embodiment of the invention, the HCA ispresent from about 50% to about 96% of the total weight of theHCA-containing compound. In one embodiment of the invention, the one ormore lubricants are present from about 0.0001% to about 50% of the totalweight of the of the HCA-containing compound. In one embodiment of theinvention, the one or more lubricants are present from about 0.001% toabout 50% of the total weight of the of the HCA-containing compound. Inone embodiment of the invention the one or more lubricants are presentfrom about 0.01% to about 50% of the total weight of the of theHCA-containing compound.

In one aspect of the invention, the HCA-containing compounds in include,HCA, one or more absorption-enhancer/controlled-release agents, and ormore lubricants. In one embodiment of the invention, the HCA is presentfrom about 1.0% to about 80% of the total weight of the HCA-containingcompound. In one embodiment of the invention, the HCA is present fromabout 5% to about 70% of the total weight of the HCA-containingcompound. In one embodiment of the invention, the HCA is present fromabout 10% to about 60% of the total weight of the HCA-containingcompound. In one embodiment of the invention, the one or moreabsorption-enhancer/controlled-release agents are present from about1.0% to about 50% of the total weight of the HCA-containing compound. Inone embodiment of the invention, the one or moreabsorption-enhancer/controlled-release agents are present from about1.0% to about 40% of the total weight of the HCA-containing compound. Inone embodiment of the invention, the one or moreabsorption-enhancer/controlled-release agents are present from about1.0% to about 30% of the total weight of the HCA-containing compound. Inone embodiment of the invention, the one or more lubricants are presentfrom about 0.0001% to about 10% of the total weight of the of theHCA-containing compound. In one embodiment of the invention, the one ormore lubricants are present from about 0.001% to about 10% of the totalweight of the of the HCA-containing compound. In one embodiment of theinvention, the one or more lubricants are present from about 0.01% toabout 5% of the total weight of the of the HCA-containing compound.

In one embodiment of the invention, the HCA-containing compound isincluded in a pharmaceutical composition containing apharmaceutically-acceptable carrier.

In one aspect, the invention provides a method of suppressing theappetite in a subject, by administering to a subject in which appetitesuppression is desired an HCA-containing compound of the invention in anamount sufficient to suppress the appetite in the subject.

In one aspect, the invention provides a method of reducing thecytoplasmic citrate lyase activity in a subject, by administering to asubject in which reducing cytoplasmic citrate lyase activity is desiredan HCA-containing compound of the invention in an amount sufficient toreduce the citrate lyase activity.

In one aspect, the invention provides a method of increasing the fatmetabolism in a subject, by administering to a subject in whichincreased fat metabolism is desired an HCA-containing compound in anamount sufficient to increase fat metabolism:

In one aspect, the invention provides a method of inducing weight-lossin a subject, by administering to a subject in which weight-loss isdesired an HCA-containing compound in an amount sufficient to induceweight-loss.

In one aspect, the invention provides a method of reducing blood lipidsand postprandial lipemia in a subject, by administering to a subject inwhich reduced blood lipids and postprandial lipemia is desired anHCA-containing compound in an amount sufficient to reduce blood lipidsand postprandial lipemia.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

A “subject,” as used herein, is preferably a mammal, such as a human,but can also be an animal, e.g., domestic animals (e.g., dogs, cats andthe like), farm animals (e.g., cows, sheep, pigs, horses and the like)and laboratory animals (e.g., rats, mice, guinea pigs and the like).

An “effective amount” of an HCA-containing compound of the invention, asused herein, is a quantity sufficient to achieve a desired therapeuticand/or prophylactic effect, for example, an amount which results in theprevention of or a decrease in the symptoms associated with a disease,disorder or condition that is being treated, e.g., obesity, weight gain,hunger, hyperlipemia, postprandial lipemia. The amount of anHCA-containing composition of the invention administered to the subjectwill depend on the type and severity of the disease, disorder orcondition, and on the characteristics of the individual, such as generalhealth, age, sex, body weight and tolerance to drugs. It will alsodepend on the degree, severity and type of disease. The skilled artisanwill be able to determine appropriate dosages depending on these andother factors. Typically, an effective amount of the HCA-containingcompound of the invention sufficient for achieving a therapeutic orprophylactic effect will range from about 0.000001 mg per kilogram bodyweight per day to about 10,000 mg per kilogram body weight per day. Inone embodiment, the dosage ranges are from about 0.0001 mg per kilogrambody weight per day to about 100 mg per kilogram body weight per day. Acommon dosage range is between 1,000-5,000 mg per day. Another commondosage range is between 2,000-3,000 mg per day. A common daily dose is3,000 mg per day. The HCA-containing compound of the invention can alsobe administered in combination alone, or with one or more additionaltherapeutic compounds.

II. General

It is an object of the present invention to provide stable,non-hygroscopic HCA-containing compounds, e.g., potassium HCA, usefulunder those conditions necessary for tableting, encapsulation, theproduction of controlled-release vehicles and that can be incorporatedinto dry powders. Accordingly, the present invention teaches the use ofabsorption-enhancer/controlled-release agents and rate-controllingexcipients for modifying the hygroscopic and other properties of HCAsalts to stabilize and control the delivery of salts and derivatives ofHCA. The invention provides methods to render non-hygrospcopic andstable, e.g., not prone to lactonization or acid-catalyzed degradationor sequestration by agents that inhibit their absorption or lead totheir excretion, the otherwise hygroscopic salts of HCA in theirrelatively pure and active forms including, but not limited to potassiumHCA salt, sodium HCA salt, and other HCA derivatives. The methods of theinvention are useful to reduce the polar/ionic qualities of MCA saltsand derivatives when presented to the intestinal lumen to provideadvantages in absorption.

In one embodiment, the HCA-containing compounds of the invention includeHCA, one or more absorption-enhancer/controlled-release agents and oneor more rate-controlling excipients. The HCA can include, e.g., HCA freeacid; HCA salts; HCA derivatives; or any combination thereof. In oneembodiment, the HCA concentration is from about 1.0% to about 80% of thetotal weight of the HCA-containing compound. In one embodiment, the HCAconcentration is from about 5% to about 70% of the total weight of theHCA-containing compound. In another embodiment, the HCA concentration isfrom about 10% to about 60% of the total weight of the HCA-containingcompound.

The useful absorption-enhancer/controlled-release agents can include,but are not limited to, e.g., d-alpha-tocopheryl polyethylene glycolsuccinate (TPGS); Lubritab®; volcanic oils (e.g., such as glycerolmonostearate, cetyl alcohol, stearyl alcohol); and/or various highviscosity grades of conjugated polyethylene glycol; ethylcellulose,carboxymethylcellulose, cellulose propionate (lower, medium or highermolecular weight), cellulose acetate propionate; cellulose acetatebutyrate; cellulose acetate phthalate (CAP); cellulose triacetate;hydroxypropyl-methylcellulose phthalate; polymethyl methacrylate;polyethyl methacrylate; polybutyl methacrylate; polyisobutylmethacrylate; polyhexyl methacrylate; polyisodecyl methacrylate;polylauryl methacrylate; polyphenyl methacrylate; polymethyl acrylate;polyisopropyl acrylate; polyisobutyl acrylate; polyoctadecyl acrylate;polyethylene; polyethylene low density; polyethylene high density;polypropylene; polyethylene oxide; polyethylene terephthalate; polyvinylisobutyl ether, polyvinyl acetate; polyvinyl acetate phthalate;polyvinyl chloride; polyurethane; other copolymers of acrylic andmethacrylic and esters; waxes; shellac; zein (vegetable protein of theprolamine group); hydrogenated vegetable oils; polyvinyl alcohol;polyvinylpyrrolidone; methyl cellulose; hydroxypropyl cellulose;hydroxpropylmethyl cellulose or polyethylene glycol; or a mixturethereof. In one embodiment, the absorption-enhancer/controlled-releaseagent concentration is from about 1.0% to about 50% of the total weightof the HCA-containing compound. In another embodiment, theabsorption-enhancer/controlled-release agent concentration is from about1.0% to about 40% of the total weight of the HCA-containing compound. Inyet another embodiment, absorption-enhancer/controlled-release agentconcentration is from about 1.0% to about 10% of the total weight of theHCA-containing compound. In yet another embodiment,absorption-enhancer/controlled-release agent concentration is from about2.0% to about 8.0% of the total weight of the HCA-containing compound.

The useful rate-controlling excipients can include, but are not limitedto, e.g., polymers, plasticizers and disintegrants. The rate-controllingexcipients can be hydrophobic. The rate-controlling excipients, e.g.,plasticizers are useful to prevent the polymer shielding the HCA frombecoming too brittle and cracking. The rate-controlling excipients arealso useful to wick fluid into the matrix of the tablets, etc. Theuseful rate-controlling excipients can include, but are not limited to,e.g., Eastacryl® (dispersion of cellulose acetate pthalate); Kollicoat®IR (polyvinylalcohol-polyethyleneglycol graft-copolymer); celluloseacetate phthalate; Kollicoat® SR (polyvinylacetate dispersion stabilizedwith povidone and sodium laurylsulfate,); ethyl cellulose; Eudragit®(family of acrylate and methacrylate-based coatings); zein (vegetableprotein); acrylic polymers; polyvinyl acetate phthalate;hydroxymethylpropylmethyl cellulose phthalate; cellulose acetatetrimalleate; acrylic polymer plasticizers; polymers of polylactic acid;polymers of glycolic acid, and mixtures thereof; Primogel; Pruv™(stearyl fumarate sodium); citrate esters; triethyl citrate; propyleneglycol; and dibutyl sebacate. In one embodiment, the rate-controllingexcipient concentration is from about 0.0001 to about 60% of the totalweight of the HCA-containing compound. In one embodiment, therate-controlling excipient concentration is from about 0.001% to about50% of the total weight of the HCA-containing compound. In anotherembodiment, the rate-controlling excipient concentration is from about0.01% to about 25% of the total weight of the HCA-containing compound.

Kollicoat® IR (polyvinylalcohol-polyethyleneglycol graft-copolymer) isan instant-release coating useful to create an HCA granulate compositionfor further processing that does not Immediately become gummy whensubjected to moisture and other challenges. Kollicoat®SR is a stabilizedpolyvinylacetate dispersion that provides a sustained-release coating.Eastacryl from Eastman is a dispersion of CAP used to provide asustained-release coating.

In another embodiment, the HCA-containing compounds of the inventioninclude HCA, one or more absorption-enhancer/controlled-release agents;one or more rate-controlling excipients; and one or more lubricants. Alubricant aids tablet manufacture by reducing friction in the tablet dieduring the act of compaction/compression and also during ejection. Thelubricants improve powder flow characteristics, preventing the tabletsfrom sticking to the punches, etc. Useful lubricants can include, butare not limited to, e.g., stearates (e.g., magnesium stearate, calciumstearate and sodium stearate, glycerol monostearate and stearic acid);Lubritab®; hydrogenated vegetable oils; waxes; talc; boric acid; sodiumbenzoate; sodium acetate; sodium chloride; DL-leucine; sodium oleate;sodium lauryl sulfate; magnesium lauryl sulfate and polyethylene glycolsand kaolin. In one embodiment, the lubricant concentration is from about0.0001 to about 10% of the total weight of the HCA-containing compound.In one embodiment, the lubricant concentration is from about 0.001% toabout 10% of the total weight of the HCA-containing compound. In anotherembodiment, the lubricant concentration is from about 0.01% to about 5%of the total weight of the HCA-containing compound.

Lubritab® (hydrogenated vegetable oil, Type 1, NF; hydrogenated oil JP;hydrogenated oil JP; and hydrogenated vegetable oil, BP is made fromfully hydrogenated refined vegetable oil that is sprayed into a dry,fine powder) is useful in the HCA-containing compounds of the inventionas a lubricant. It is also useful as an auxiliary dry binder whentablets and capsules tend to cap or laminate. Lubritab® at up to 5% ofthe total weight of the HCA-containing compound can eliminate theseproblems and aid in producing satisfactory HCA-containing tablets.Lubritab® is more effective as a lubricant for HCA-containing compoundswhen added in the dry state in the last blending operation beforecompression and blending for 10-15 min. Lubritab® is useful as alubricant in HCA-containing compounds of the invention when used inconjunction with an anti-adherent. An anti-adherent prevents the tabletfrom sticking to the tablet punch and to the die wall. Anti-adherentscan include, but are not limited to, e.g., talc, corn starch, colloidalsilicon dioxide, DL-leucine, sodium lauryl sulfate, and metallicstearates. Some ingredients, such as talc, can act in the sameformulation as a lubricant, an anti-adherent and a glidant. A glidantimproves the flow characteristics of the granulate. Glidants include,e.g., talc, corn starch and colloidal silicon dioxides, such as Aerosil™(Degussa).

Furthermore, Lubritab® is useful in the HCA-containing compounds of theinvention in controlled-release applications. In one embodiment,Lubritab® is used at 20-40% of the total weight of the HCA-containingcompound. In another embodiment, Lubritab® is used at from about 5% toabout 40% of the total weight of the HCA-containing compound. Oneskilled in the art will recognize that magnesium stearate, otherstearates, hydrogenated vegetable oils and related compounds similarlycan be adapted to the purpose of controlling the release of HCA saltsand compounds.

In another embodiment, the HCA-containing compounds of the Inventioninclude HCA, one or more absorption-enhancer/controlled-release agents;one or more rate-controlling excipients; and one or morebulking-agents/binders. These bulking-agents/binders are also useful tomodulate the HCA release rate. Useful bulking-agents/binders include,but are not limited to, e.g., starch paste; acacia; sucrose; poly vinylpyrrolidone (PVP); hydroxy proplyl methyl cellulose (HPMC); methylcellulose; and gelatin. In one embodiment, water-wicking agents, such asmicrocrystalline cellulose, are used in the HCA-containing compound ofthe invention to regulate how fast a controlled-release tablet ispenetrated when it reaches a high pH region. In another embodimentdisintegrants are useful as bulking agents in the HCA-containingcompounds of the invention. Useful disintegrants include, but are notlimited to, e.g., potato starch; micro crystalline cellulose (MCC);pregelatinized starch (PGS); Primogel (Sodium starch glycolate, USP/NF,Ph. Eur.); Primellose (Crosscarmelose sodium, USP/NF, ph. Eur.)

The useful bulking-agents/binders can include, but are not limited to,e.g., di-calcium phosphate and tri-calcium phosphate. In one embodiment,the bulking agent/binder concentration is from about 0.01% to about 30%of the total weight of the HCA-containing compound. In one embodiment,the bulking agent/binder concentration is from about 0.1% to about 30%of the total weight of the HCA-containing compound. In anotherembodiment, the bulking agent/binder concentration is from about 0.1% toabout 25% of the total weight of the HCA-containing compound.

In yet another embodiment, the HCA-containing compounds of the inventioninclude HCA, one or more absorption-enhancer/controlled-release agents;one or more rate-controlling excipients; one or more lubricants; and oneor more bulking-agents/binders.

In yet another embodiment, the HCA-containing compounds of the inventioninclude HCA and one or more rate-controlling excipients.

In yet another embodiment, the HCA-containing compounds of the inventioninclude HCA and one or more lubricants.

In yet another embodiment, the HCA-containing compounds of the inventioninclude HCA, one or more absorption-enhancer/controlled-release agents;and one or more lubricants.

In another embodiment, the aforementioned HCA-containing compounds ofthe invention have chloride content of less than about 2.5% weight. Inone embodiment, the chloride content of the HCA-containing compound ofthe invention is less that about 1.0% weight. In yet another embodiment,the chloride content of the HCA-containing compound of the invention isless than about 0.5% weight.

In yet another embodiment, the aforementioned HCA-containing compoundsof the invention have a total halogen content as chloride of less thanabout 2.9% weight. In one embodiment, the HCA-containing compounds ofthe invention have a total halogen content as chloride of less thanabout 1.0% weight. In yet another embodiment, the HCA-containingcompounds of the invention have a total halogen content as chloride ofless than about 0.6% weight.

In one embodiment, the HCA-containing compounds of the invention areincluded in a dry delivery system, e.g., tablet, dry powder, and drymeal replacement mixture. In another embodiment, the HCA-containingcompounds of the invention are included in a liquid delivery system,e.g., capsule, caplet, or beverage. In yet another embodiment, theHCA-containing compounds of the invention are used in controlled-releasevehicles, e.g., tablet, caplet, and capsules.

The present application is related to U.S. Pat. No. 6,447,807, issuedSep. 10, 2002, the contents of which are hereby incorporated byreference in its entirety.

Ill. Characteristics of HCA and HCA Salts

Early work ascribed the weight loss benefit to HCA, its salts and itslactone form. See generally, U.S. Pat. No. 3,764,692 granted to John M.Lowenstein. One commonly offered explanation for the biological andtherapeutic effects of HCA is the inhibition of cytoplasmic (cytosolic)ATP-citrate lyase (D. Clouatre and M. E. Rosenbaum, The Diet and HealthBenefits of HCA (Hydroxicitric Acid), 1994). In subsequent studies thelactone form of HCA was shown to be far less effective than the sodiumsalt form of HCA for weight loss purposes, in part because the lactoneform lacks the proper affinity for ATP-citrate lyase, known to be atarget of the actions of HCA (Lowenstein and Brunengraber, MethodsEnzymol. 1981; 72:486-97). Under conditions that promote lactonization(e.g., acidic conditions), free HCA undergoes rapid inactivation.Indeed, inclusion of currently available mineral salts of HCA in aprepared beverage of acidic pH leads to the development of HCA lactoneover time.

The use of free HCA concentrate in food products has been described inU.S. Pat. No. 5,536,516, but it does not teach any particular advantagefor the use of HCA in weight loss or for other medicinal purposes. Evenbrief exposure of the potassium and sodium salts of HCA to acidicconditions or flavored beverages results in chemical changes in theseHCA salts. In some cases the beverages actually change color uponaddition of potassium HCA or sodium HCA salts.

Free HCA is extremely ionic and does not pass readily through the gutmembrane. The free acid form of HCA can be sequestered by bindingsoluble and insoluble fibers as well as by many other compounds, thusrendering HCA biologically unavailable. There is evidence that the freeHCA and HCA lactone are both irritating to the gastrointestinal tissuesif consumed regularly in large amounts.

Generally, calcium HCA and magnesium HCA salts, either alone or in theform of various mixtures together, or in combination with the potassiumHCA and sodium HCA salts, are not preferred delivery forms for HCA.Calcium HCA and magnesium HCA salts are also not readily absorbed acrossthe gastrointestinal tract because they are poorly soluble in aqueousmedia. These HCA salts are also reactive with bile acids and fats in thegut and/or are sequestered by binding to soluble and insoluble fibers orother substances in the diet or secreted during digestion (Heymsfield,Steven B, et al. JAMA 1998; 280(18): 1596-1600; Letters, JAMA 1999; 282:235). For example, the action of stomach acid may free one of the twovalences of calcium HCA or magnesium HCA salts for attachment to fats,bile acids, gums, fibers, pectins, and so forth and so on, which is anundesirable outcome. The addition of small amounts of magnesium HCA topotassium HCA, however, improves the transit of potassium HCA acrosscell membranes. By contrast, calcium, impedes the transit of potassiumHCA across cell membranes.

Calcium/potassium HCA (Super CitriMax®) is not well absorbed as only 20%of the dose ingested by fasted subjects was detected in the blood usinggas chromatography/mass spectroscopy technique (Loe et al., AnalBiochem. 2001, 1; 292(1): 148-54). Loe and coworkers reported that theabsorption of calcium/potassium HCA (Super CitriMax®) peaked 2 hoursafter administration, and that the compound remained in the blood formore than 9 hours after ingestion (Loe et al., FASEB Journal, 15 4:632,Abs. 501.1, 2001). Eating a meal shortly after taking Super CitriMax®reduced its absorption by about 60%. Moreover, animal trials (see U.S.Pat. No. 6,476,071) have further demonstrated that in order for thepotassium salt to be maximally effective, the ligand must be fully boundto the HCA with only trivial amounts of contaminants, including mostother minerals or fibers or sugars.

Calcium HCA salt has some further disadvantages that may limit itstherapeutic use. Calcium uptake from the gut is highly regulated andunder normal circumstances does not exceed approximately 35% of thatfound in foods and supplements. The uptake of calcium declines as thedosage of calcium is increased. This may limit the use of calcium HCAwhere large doses may need to be ingested. For example, for weight lossand other purposes, a minimally effective amount of HCA derived from itscalcium salt requires the administration of between 12 and 15 grams of a50% material. This amount of calcium HCA may lead to undesirablyelevated levels of binding and excretion of other dietary minerals, suchas zinc, aside from presenting difficulties in administration.

HCA sodium salt has disadvantages for long-term administration to asubject. First, sodium HCA lacks positive metabolic effects with regardto obesity. Second, sodium HCA has potential hypertensive actions.Indeed, several of the early Indian-supplied “potassium” salts were, infact, mixtures of calcium, potassium and sodium (−)-hydroxycitrate. Theamount of sodium in these HCA preparations exceeded that allowed in lowsodium diets notwithstanding the fact that added sodium is ill-advisedin any modern diet. In contrast, potassium HCA does not possess thedisadvantages associated with sodium HCA.

A preferred salt of HCA for pharmaceutical use is potassium HCA. Themineral potassium is fully soluble, as is its HCA salt, and is known topossess cell membrane permeability which is 100 times greater than thatpossessed by sodium. However, the potassium salt of HCA, as is also trueof the sodium salt, is extremely hygroscopic and thus not suitable undernormal circumstances for the production of dry delivery forms. Indrawing moisture to itself, potassium HCA will also tend to bind toavailable binding sites of compounds in its immediate environment, andthis action often later will markedly impede the assimilation ofpotassium HCA from the gut. Potassium HCA is also not suitable forliquid delivery forms inasmuch as potassium HCA in solution will slowlylactonize to an equilibrium which is dependent upon the pH.

IV. Select HCA-Containing Compounds and their Delivery

Several international patent applications and U.S. patents discloseHCA-containing compounds and its delivery as calcium, magnesium andadmixtures of salts. International patent application WO 99/03464, filed28 Jan. 1999, is directed to HCA-containing compounds with 14 to 26 wt %calcium HCA, and approximately 24 to 40 wt % potassium HCA orapproximately 14 to 24 wt % sodium HCA, or a mixture thereof, eachcalculated as a percentage of the total HCA content of the compositionfor use in dietary supplements and food products. Studies assessing sucha composition showed that its assimilation is exceedingly poor even whentaken on an empty stomach (Loe et al., Anal Biochem. 2001 May 1; 292(1):148-54) and that eating a meal shortly after taking it reduced itsabsorption by about 60% (Loe et al., Time Course of HydroxycitrateClearance in Fasting and Fed Humans, FASEB Journal, 15, 4: 632, Abs.501.1, 2001). Further, studies comparing the effect of variousHCA-containing compounds on body weight and food intake in a rat obesitymodel showed that a test composition of calcium/potassium HCA saltidentical to that described by WO 99/03464 was inferior compared topotassium HCA salt in reducing weight gain in middle-aged rats fed a 30%fat diet (see U.S. Pat. No. 6,476,071 B1). Specifically, at the level ofintake used experimentally on a 30% fat diet, potassium HCA increasedprotein as a percentage of body weight while reducing fat as apercentage of body weight. In contrast, the calcium/potassium salt HCAtest composition increased fat and reduced protein as percentages ofbody weight.

International patent application WO 00/15051 is directed to a method ofmaking calcium HCA more soluble by under-reacting the material, i.e.,leaving a substantial amount of HCA lactone in the finished product.This procedure, however, does little to improve the uptake of HCA. Theproblems with HCA lactone are discussed above, and the HCA lactone inlarge amounts is known to be irritating (Ishihara et al., J Nutr. 2000December; 130(12): 2990-5). Making calcium soluble, again, does nothingto prevent its reactivity with compounds in the gut, e.g., bile salts,or to improve the general rate of assimilation of calcium HCA. It isnoteworthy that the process disclosed in WO 00/15051 was previouslydisclosed by others in 1997 (Sawada et al., Journal of Japan Oil andChemicals/Nihon Yukagaku Kaishi 1997 December; 46, 12: 1467-1474) andmany months earlier in Japanese.

International patent application WO 02/014477 is directed to acomposition comprising HCA in combination with either one or both ofgarcinol and anthocyanin. Garcinol is a common contaminant of HCAproducts, and thus, it is typically present in the salts which have beenused for other clinical studies, i.e., extracts rather than synthesizedpure HCA salts. It is unknown whether the additive effect shown in WO02/014477 extends beyond the mild response reported if higher dosages ofeither component are ingested. However, a published paper examining theimpact of flavonoids derived from Garcinia cambogia found that a doseresponse study revealed biphasic activity. Higher doses were lesseffective in reducing lipid levels in serum and tissues, although devoidof toxic effects. (Koshy A S, Vijayalakshmi N R. Impact of certainflavonoids on lipid profiles—potential action of Garcinia cambogiaflavonoids. Phytother Res. 2001 August; 15(5):395-400.)

U.S. Pat. No. 6,221,901 is directed to the preparation and uses ofmagnesium HCA. The high dosage of magnesium HCA required to achieve theindicated results, however, may limit therapeutic utility of thecomposition. For example, in order to achieve a hypotensive effect, forinstance, the inventors fed their animals 500 mg/kg magnesium HCA. Usingthe standard 5:1 multiplier for rat to human data, the dose of magnesiumhydroxycitrate employed by Shrivastava et al. is equivalent to a humaningesting 100 mg/kg/day or 7 grams for the average-sized human subject.Of this amount, 45% would be elemental magnesium; hence resulting in ahuman ingesting the equivalent of approximately 3.15 grams of magnesium.The Recommended Dietary Allowances, 10th edition (National ResearchCouncil, 1989), indicates that most humans begin to suffer diarrhea atmore than 350 mg/day. In other words, the test dose used by Shrivastavaat al. is nearly 10 times the dose at which side effects would normallybe expected to begin to appear. The induced diarrhea itself would lowerblood pressure rapidly.

U.S. Pat. No. 5,783,603 is directed to a technique for the production ofpotassium HCA. The potassium HCA prepared by this method requires thatthe milling, sifting, blending and packing of the potassium HCA becarried out in a nitrogen atmosphere as the potassium HCA preparation isotherwise hygroscopic. That is, if left in the open air outside of ahumidity-controlled environment, the potassium HCA produced according tothat patented method will begin to absorb moisture within a few min.This property will limit the use of this material as a component of drypharmaceutical or nutraceutical preparations. There are available low-pHversions of potassium HCA, i.e., pH of between 7 and 8, but such formsof potassium hydroxycitrate are under-reacted, infused with lactone, orsuffer similar failings which make them inferior in the physiologicaleffects to the properly prepared product. A fully reacted potassium HCAwill have a pH greater than 9.

U.S. Pat. No. 6,447,807 is directed to methods for making thehygroscopic salts of HCA workable and for controlling the delivery ofHCA salts. The methods of the present invention are distinct from themethods of the issued patent as they teach the use of TPGS. The use ofTPGS in the preparation of HCA-containing compounds improves upon themethods of U.S. Pat. No. 6,447,807 by reducing or eliminating both theneed to spray-dry HCA onto a separate carrier, e.g., maltodextan andsteps requiring special spray or freeze drying of the HCA-containingcompound.

V. HCA Delivery

The effective delivery of HCA to a subject in need thereof has beenlimited by the few methods for producing a controlled-release form ofHCA, regardless of the salt used. Tests performed to establish theappetite-suppressing effects of HCA demonstrated that a single largeoral dose or two divided oral doses totaling one fourth the size of thesingle dose resulted in a 10% or greater reduction in food consumptionin experimental animals fed a high-sugar diet. This result continuedover many weeks with the chronic ingestion of HCA. The requirement forat least two divided doses of HCA for efficacy is the only thoroughlyestablished procedure to date.

Giving HCA as multiple doses, as is true of any drug, is inconvenientand is not supported by good patient compliance. Multiple doses given inthe form of any of the current salts is also wasteful in that anymaterial delivered to the body which is above the baseline or thresholdnecessary to produce benefits is simply an excess which is excreted.Controlled release of HCA avoids both excess and waste, on the one hand,and gaps in coverage, on the other hand. Controlled release makes itpossible to simplify the dosage schedule to one daily administration.Moreover, it is to be expected that a smaller amount of HCA delivered bycontrolled release will provide benefits which are superior to thosefound with a larger amount of HCA supplied after a normal fashion in atleast two dosages.

As noted above, the potassium salt of HCA is the most efficacious formof HCA to be used for human weight loss and for other pharmaceuticaland/or nutraceutical purposes, followed secondarily for these purposesby the sodium salt. The potassium and the sodium salts of HCA presentvery similar difficulties in handling and manipulation. Potassium HCA isextremely hygroscopic and tends to bind with water in the open air toform a non-palatable paste not suitable for use in tablets, capsules orpowders. This material can be admixed with orange juice or water, butrequires vacuum pouch sealing under a humidity-controlled atmosphere andis inconvenient for the patient to use. Potassium HCA is reactive with alarge number of compounds (tannins, gums, fibers, pectins, and so forth)are thereby readily suffers large losses in pharmacologicalavailability.

VI. Granulation of HCA-Containing Compounds and the Use of TPGS

It is a known pharmaceutical practice to cover material to begranulated, especially hygroscopic materials, with molten oils such ashydrogenated vegetable oil, glycerol monostearate, cetyl alcohol,stearyl alcohol and various high viscosity grades of conjugatedpolyethylene glycol. The use of TPGS in the HCA-containing compounds wasnot previously known.

TPGS has a melting point of 40° C. and is as water soluble aspolyethylene glycol. TPGS is synthesized by esterifyingd-alpha-tocopheryl succinate with polyethylene glycol (PEG) 1000 (i.e.,the molecular weight of PEG 1000 is approximately 1,000 daltons). Theresulting product is a pale yellow, waxy solid substance that isamphipathic and hydrophilic with a molecular weight of approximately1,513 daltons. d-alpha-Tocopherol comprises 26% of TPGS. TPGS isvariously known as d-alpha-tocopheryl polyethylene glycol 1000 succinateand d-alpha-tocopheryl d-alpha-tocopheryl PEG 1000 succinate. Inasmuchas there are eight stereoisomers of alpha-tocopherol, more completechemical names for TPGS include RRR-alpha-tocopheryl polyethylene glycol1000 succinate, 2R,4′R, 8′R-alpha-tocopheryl polyethylene glycol 1000succinate and2,5,7,8-tertramethyl-2-(4′,8′,12′-trimethyltridecyl)-6-chromanylpolyethylene glycol 1000 succinate. PDRhealth, an online-component ofthe Medical Economics Company (seehttp://www.gettingwell.com/drug_info/nmdrugprofiles/nutsupdrugs/alp_(—)0091.shtml,which provides a description of the pharmacokinetics of TPGS). It isanticipated that, in the future, other isomers of tocopherol will becomeavailable for the uses proposed here as natural extensions of the art.Such extensions of the art are contemplated to be within the scope ofthe present invention.

TPGS has the capability to act as an emulsifying agent in theformulation of organic water-based emulsions and can be used as a moltendirect spray on certain products that have low bioavailability. Theproduct has an HLB (hydrophile/lipophile balance) of ˜13. It is stableto air, but reacts with alkali. TPGS can serve as an excellent coatingfor granulated material or oils which have low intestinal absorption.TPGS also has benefits over many other chemicalnon-nutritive/non-natural emulsifiers.

The product is structurally similar to an amphiphile. It has a dualnature, with part of the molecule comprising the hydrophilic polar headand the other liphophilicity. The exact portion of the moleculecomprising the hydrophilic or polar end head or the lipophilic alkyltail cannot be elucidated from the molecular structure. The generallyaccepted view is that the polyethylene glycol portion serves as thehydrophilic polar head while the tocopheryl succinate portion serves asthe lipophilic tail. TPGS provides vitamin E at 387-447 IU/g. Thismaterial is melted using a hot plate or other device and stirred with amagnetic stirring rod at a temperature of approximately 40° C. orhigher. It is then sprayed onto the material to be granulate in a fluidbed dryer using an inlet temperature of approximately 30° C. and thespray is adjusted so as to place a fine mist over the material to begranulated. As soon as the powder is thoroughly blended with the moltenphase and dried to a hard solid surface, a second coat of hydrogenatedoil is applied.

This overcoat of solid oil is preferably molten hydrogenated vegetableoil. This material is purely lipophilic and has little or no amphiphiliccharacter to its nature. It is made into a molten phase by heating andstirring while spraying onto the powder with previously granulated TPGS.Over these two oil layers is sprayed and dispersed the rate-controllingpolymer or polymers.

TPGS improves the uptake of cyclosporin and many other compounds.Vitamin E TPGS is also used in the solvent extraction/evaporationtechnique for fabrication of polymeric nanospheres of an antineoplasticdrug Paclitaxel (Taxol®) for cancer chemotherapy (BED-Vol. 50, 2001Bioengineering Conference ASME 2001). The hypothesis that HCA-containingcompounds may benefit from the self-micelle-forming properties of TPGSled to studies assessing the effect of TPGS on the stability andhygroscopic nature of HCA-containing compounds. Studies assessing theeffect of formulating HCA-containing preparations with TPGS demonstratedthat TPGS is especially well-suited for granulation of HCA-containingcompounds and enhances their bioavailability. That is, the inventorshave been successful in granulating the potassium salt form of HCA intoa workable powder. This workable powder can be further manipulatedaccording to the procedures taught in the U.S. Pat. No. 6,447,807 toproduce a product formulated for controlled delivery. The same resultscan be extended to sodium and other salts of HCA and their mixtures.

As noted above, U.S. Pat. No. 6,447,807 is directed to methods formaking the hygroscopic salts of HCA workable and for controlling thedelivery of HCA salts. The methods of the present invention are distinctfrom the methods of the issued patent as they teach the use of TPGS. Theuse of TPGS in the preparation of HCA-containing compounds improves uponthe methods of U.S. Pat. No. 6,447,807 by reducing or eliminating boththe need to spray-dry HCA onto a separate carrier, e.g., maltodextan andsteps requiring special spray or freeze drying of the HCA-containingcompound. The present invention can substitute fluid bed drying forthese latter processes.

VII. HCA-Containing Compounds

HCA-containing compounds of the invention which include, but not limitedto, e.g., HCA free acid, HCA salts, HCA derivatives, or any combinationthereof, to make a granulate which can be used alone or furtherformulated with pharmaceutically acceptable compounds, vehicles, oradjuvants with a favorable delivery profile, i.e., suitable for deliveryto a subject. Such compositions typically comprise the HCA-containingcompound of the invention and a pharmaceutically acceptable carrier. Asused herein, “pharmaceutically acceptable carrier” is intended toinclude any and all solvents, dispersion media, coatings, antibacterialand antifungal compounds, isotonic and absorption delaying compounds,and the like, compatible with pharmaceutical administration. Suitablecarriers are described in the most recent edition of Remington'sPharmaceutical Sciences, a standard reference text in the field, whichis incorporated herein by reference. Examples of such carriers ordiluents include, but are not limited to, water, saline, Ringer'ssolutions, dextrose solution, and 5% human serum albumin. Liposomes andnon-aqueous vehicles such as fixed oils may also be used. The use ofsuch media and compounds for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or compoundis incompatible with the active compound, use thereof in thecompositions is contemplated. Supplementary active compounds can also beincorporated into the compositions.

A pharmaceutical composition of the Invention is formulated to becompatible with its Intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical),transmucosal, and rectal administration. The pH can be adjusted withacids or bases, such as hydrochloric acid or sodium hydroxide.

Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed in gelatin capsules, caplets or compressedinto tablets. For the purpose of oral therapeutic administration, theHCA-containing compound of the invention can be incorporated withexcipients and used in the form of tablets, troches, or capsules. Oralcompositions can also be prepared using a fluid carrier for use as amouthwash, wherein the compound in the fluid carrier is applied orallyand swished and expectorated or swallowed. Pharmaceutically compatiblebinding compounds, and/or adjuvant materials can be included as part ofthe composition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegratingcompound such as alginic acid, Primogel, or corn starch; a lubricantsuch as magnesium stearate or Sterotes; a glidant such as colloidalsilicon dioxide; a sweetening compound such as sucrose or saccharin; ora flavoring compound such as peppermint, methyl salicylate, or orangeflavoring.

The HCA-containing compound of the invention can also be prepared aspharmaceutical compositions in the form of suppositories (e.g., withconventional suppository bases such as cocoa butter and otherglycerides) or retention enemas for rectal delivery.

In one embodiment, the HCA-containing compounds of the invention areprepared with carriers that will protect the compound against rapidelimination from the body, such as a controlled release formulation,including implants and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylenevinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Methods for preparation of suchformulations will be apparent to those skilled in the art. The materialscan also be obtained commercially from Alza Corporation and NovaPharmaceuticals, Inc. Liposomal suspensions can also be used aspharmaceutically acceptable carriers. These can be prepared according tomethods known to those skilled in the art, for example, as described inU.S. Pat. No. 4,522,811.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the Invention are dictated by and directlydependent on the unique characteristics of the HCA-containing compoundand the particular therapeutic effect to be achieved, and thelimitations inherent in the art of compounding such an active compoundfor the treatment of individuals.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

VIII. Methods of Preparing HCA-Containing Compound Using TPGS

TPGS can be applied to a dry HCA preparation including, but not limitedto, e.g., HCA free acid, HCA salts, HCA derivatives, or any combinationthereof, to make a granulate which can be used alone or furtherformulated with pharmaceutically acceptable compounds, vehicles, oradjuvants with a favorable delivery profile, i.e., suitable for deliveryto a subject. (−)-Hydroxycitric acid and its lactone, which are liquids,can be made amenable for employment in this invention by first beinglaid upon a suitable desiccant, e.g., fumed silicon dioxide, as taughtin U.S. Ser. No. 10/303,117 (Clouatre, Clouatre and Dunn), in whichexamples include liquid potassium HCA. The HCA preparations of theinvention may be administered to a subject in need thereof by anysuitable route, including, but not limited to, e.g., oral,intraperitoneal, and intravenous. In one embodiment the HCA preparationof the invention is administered to a subject one or more times a day.In one embodiment, the HCA preparation of the invention is administeredto a subject once a day.

HCA, HCA salts and HCA derivatives can be prepared as conjugates withlipids, the primary agent being TPGS. Further preparation withtime-released polymers, when compounded as a controlled release tabletor capsule, provides prolonged dwell time in the body after oraladministration. Mucosal adhesive and similar agents can also beemployed. The amount of TPGS will normally range between 2% and 10% ofthe finished product. A similar range will be typical for hydrogenatedvegetable oils or similar items used to complement the actions of theTPGS. Methods for the preparation of HCA-containing compounds of theinvention are detailed in Examples 1 through Example 4.

Briefly, HCA, an HCA salt or a combination of HCA salts are blended in alow humidity environment with TPGS to yield a TPGS/HCA mixture. TheTPGS/HCA mixture is further blended with molten oils, such ashydrogenated vegetable oil, glycerol monostearate, cetyl alcohol,stearyl alcohol and/or various high viscosity grades of conjugatedpolyethylene glycol to yield a crude TPGS/HCA granulate mixture. Thecrude TPGS/HCA granulate mixture is then blended with a polymer whereinthe polymer to yield an HCA-containing compound of the invention. Thepolymer film should have enteric properties as taught in U.S. Pat. No.6,447,807. Suitable polymers include, but are not limited to, e.g.,cellulose acetate phthalate, ethyl cellulose, Eudragit L55®, zein,acrylic polymers, hydroxymethylpropylmethyl cellulose phthalate,polyvinyl acetate phthalate, cellulose acetate trimalleate, acrylicpolymer plasticizers, polymers of polylactic acid, polymers of glycolicacid, and mixtures thereof. The HCA-containing compound of the inventionis then formulated into tablets, capsules, prepared dry drink mixes,prepared liquid drinkable products and edible bars.

In one embodiment, the TPGS is admixed with the other components of thecomposition from about 1.0% to about 50% by weight of the amount of HCAon a dry weight basis. In one embodiment, the TPGS is admixed with theother components of the composition from about 1.0% to about 20% byweight of the amount of HCA on a dry weight basis. In anotherembodiment, the TPGS is admixed with the other components of thecomposition from about 2% to about 10% by weight of the amount of HCA ona dry weight basis.

IX. Uses of the HCA-Containing Preparation of the Present Invention

A. Prophylactic and Therapeutic Uses of the HCA-Containing Compounds

The HCA-containing compounds of the present invention are useful inpotential prophylactic and therapeutic applications implicated in avariety of disorders, diseases and conditions in a subject including,but not limited to, e.g., obesity, overweight, hunger, deficiencies infat metabolism, hyperlipemia, and postprandial lipemia (i.e., the levelof lipids in the blood following a meal). By way of a non-limitingexample, the compositions of the invention will have efficacy fortreatment of subjects suffering from the disorders mentioned in theDiseases and Disorders, infra.

B. Determination of the Pharmacokinetics or Biological Effect of theHCA-Containing Compounds

The pharmacokinetics of HCA-containing compounds, including absorption,can be determined by measuring the HCA level in the blood of subjectsadministered an HCA-containing compound using gas chromatography/massspectroscopy technique (Loe et al., Anal Biochem. 2001, 1;292(1):148-64) and as further detailed by Loe et al., (FASEB Journal,2001,15 4:632, Abs. 501.1). The assessment and comparison of thepharmokinetics of test compounds is well known in the art.

The effect of HCA-containing compounds on the activity of ATP-citratelyase can be measured using the ATP-citrate lyase assay procedure asdetailed by Houston and Nimmo (Biochim Biophys Acta 1985 Feb. 21;844(2): 233-9). A reduction in ATP-citrate lyase activity in thepresence of HCA-containing compound when compared to the level ofATP-citrate lyase activity observed in the absence of HCA-containingcompound indicates that the HCA-containing compound inhibits ATP-citratelyase enzyme.

In various embodiments of the invention, suitable in vitro or in vivoassays are performed to determine the effect of a specific HCA-basedtherapeutic and whether its administration is indicated for treatment ofthe affected tissue in a subject.

In various specific embodiments, in vitro assays can be performed withrepresentative cells of the type(s) involved in the patient's disorder,to determine if a given HCA-based therapeutic exerts the desired effectupon the cell type(s). Compounds for use in therapy can be tested insuitable animal model systems including, but not limited to rats, mice,chicken, cows, monkeys, rabbits, and the like, prior to testing in humansubjects. Similarly, for in vivo testing, any of the animal model systemknown in the art can be used prior to administration to human subjects.

C. Diseases, Disorders and Conditions

The invention provides for both prophylactic and therapeutic methods oftreating a subject at risk of (or susceptible to) a disease or having adisorder associated with lipid metabolism, e.g., but not limited to,obesity, overweight, deficiencies in lipid metabolism, hyperlipemia,postprandial lipemia, disorders where inhibition of inhibit cytoplasmiccitrate lyase is advantageous or physical conditions such as hunger.

The HCA-containing compounds of the present invention are useful preventor treat diseases, disorders or conditions where inhibition ofinhibition of ATP-citrate lyase is advantageous, e.g., reduction ofcholesterol level. Berkhout et al., (Biochem J. 1990 Nov. 15; 272(1):181-6) studied the effect of HCA on the activity of the low-densitylipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levelsin the human hepatoma cell line Hep G2. After 2.5 h and 18 h incubationswith HCA at concentrations of 0.5 mM or higher, incorporation of [1,5-14C]citrate into fatty acids and cholesterol was strongly inhibited.It was concluded that this decrease reflected an effective inhibition ofATP citrate-lyase. Cholesterol biosynthesis was decreased to 27% of thecontrol value as measured by incorporations from ³H₂O, indicating adecreased flux of carbon units through the cholesterol-syntheticpathway.

The HCA-containing compounds of the present invention are useful toprevent or treat diseases or disorders associated with lipid metabolism,e.g., but not limited to, obesity; overweight; hyperlipemia;postprandial lipemia; and deficiencies in lipid metabolism, e.g.,insulin resistance. Ishihara et al., (J. Nutr. 2000 December; 130(12):2990-5) studied the effect of chronic HCA administration on bothcarbohydrate utilization and lipid oxidation. The respiratory exchangeratio of test subjects was significantly lower in the HCA group duringboth resting and exercising conditions. These results suggest thatchronic administration of HCA promotes lipid oxidation and sparescarbohydrate utilization in test subjects at rest and during running.

Under conditions that elevate de novo lipogenesis in humans, HCA reducedfat synthesis and increased energy expenditure (Kovacs andWesterp-Plantenga, Society for the Study of Ingestive Behavior, AnnualMeeting, 2001, Abstr. page 27). The HCA-containing compounds of thepresent invention, therefore, are useful in diseases or disordersassociated with lipid metabolism.

The HCA-containing compounds of the present invention are useful toprevent or treat hunger and to promote satiety in a subject as theadministration of HCA to subjects has been reported to promote appetitesuppression and satiety (Westerterp-Plantenga and Kovacs, Int. J. Obes.Relat. Metab. Disord., 2002, 26(6): 870-2).

EXAMPLES

The disclosures of these references provided in this list immediatelyabove are herein incorporated in their entirety by reference thereto.

Example 1

A formulation of the following composition (see Table 1) was prepared:

TABLE 1 Amount Item # Ingredient (mg/Tablet) Percent 1 HCA calcium salt500 71.43 2 Microcrystalline cellulose 17 2.42 3 Dicalcium phosphate 456.42 4 Corn starch 9 1.28 5 TPGS 46 6.60 6 Hydrogenated vegetable oil 507.14 7 Cellulose acetate phthalate 15 2.14 8 Carbopol ® 974P Carbomer 152.14 9 Magnesium Stearate 3 0.43 TOTAL 700 100

The method of preparation was as follows:

-   1. Items #1-4 were weighed and blended in a fluid bed dryer for 4-5    min. Item #5 was then dissolved by heating to 40° C. until molten,    and stirred with a magnetic stir rod. After the powders were    blended, steady blending was continued while adding the TPGS (item    #5) as a molten liquid. The TPGS was poured in fluid until an even    granulate was formed. Next, the hydrogenated vegetable oil was    melted until molten and fluid in nature. This material was then    sprayed, while at the same time stirring with a magnetic stir rod.    Blending with air at 30° C. was continued. When all the material was    thoroughly coated and the granulate was hardened, the cellulose    acetate phthalate, which had been completely dissolved in ammoniated    water, was sprayed. Spraying was continued until all the granulate    had been covered, then allowed to dry at room temperature in the    fluid bed dryer with continuous blending. When the granulate was    dry, it was removed from the bowl, and passed through a #093 screen    using a D3 Fitzmill comminutor.-   2. When the granulate was dried and reduced in size, it was blended    in fluid bed first with Carbopol-974P. When completely blended,    magnesium stearate was added and blended for 2-3 min.-   3. The mixed granulate was then placed on a rotary press and    compressed into tablets with a weight of 700 mg and a fracture force    of 10-15 kg.

These tablets resisted disintegration for at least about 1 h withstirring in monophosphate buffer solution, pH 6.8. The phosphate buffer,pH 6.8 used during simulated intestinal disintegration was made usingpotassium phosphate, monobasic (34.02 g in 5 L water), and adjusting tothe solution to pH 6.8 using 1N sodium hydroxide. Also, there was noevidence of breakdown upon exposure with stirring to simulate gastricfluid without pepsin (HCl solution with pH 1.2) for 60 min. Inasmuch asthe tablet typically will leave an empty stomach within this period oftime, this was considered to be adequate. This compares favorably withprevious formulations of non-enteric capsules containing non-enteric HCAthat disintegrated in stomach fluids within 15-30 min and tabletsusually within the same period of time and always within less than 60min. For some purposes, 55 min under a pH of 6.8 is ideal for thetime-release of HCA from an HCA-containing compound, whereas longertime-release formulations are preferred for once-per-day dosing of anHCA-containing compound.

Example 2

A formulation of the following composition (see Table 2) was prepared:

TABLE 2 Amount Item # Ingredient (mg/Tablet) Percent 1 HCApotassium/calcium salt 500 64.93 2 Dicalcium phosphate 50 6.49 3Microcrystalline cellulose 30 3.90 4 Corn starch 5 0.65 5 TPGS 30 3.90 6Hydrogenated cotton seed oil 60 7.79 7 Cellulose acetate phthalate 303.90 8 Carbopol ® 974-P carbomer 60 7.79 9 Magnesium stearate 5 0.65TOTAL 770 100

The method of preparation was as follows:

-   1. Items #1-4 were weighed and blended in a fluid bed dryer for 4-5    min. Item #5 was then dissolved by heating to 40° C. until molten,    and stirred with a magnetic stir rod. After the powders were    blended, steady blending was continued while adding the TPGS (item    #5) as a molten liquid. The TPGS was poured in fluid until an even    granulate was formed. Next, the hydrogenated vegetable oil was    melted until molten and fluid in nature. This material was then    sprayed, while at the same time stirring with a magnetic stir rod.    Blending with air at 30° C. was continued. When all the material was    thoroughly coated and the granulate was hardened, the cellulose    acetate phthalate, which had been completely dissolved in ammoniated    water, was sprayed. Spraying was continued until all the granulate    had been covered, then allowed to dry at room temperature in the    fluid bed dryer with continuous blending. When the granulate was    dry, it was removed from the bowl, and passed through a #093 screen    using a D3 Fitzmill comminutor.-   2. When the granulate was dried and reduced in size, it was blended    in fluid bed first with Carbopol-974P. When completely blended,    magnesium stearate was added and blended for 2-3 min.-   3. The mixed granulate was then placed on a rotary press and    compressed into tablets with a weight of 700 mg and a fracture force    of 10-15 kg.

The disintegration of this novel stable HCA formulation, which wasassessed in pH 6.8 monophosphate buffer, was 3-4 hours. This comparesfavorably with previous formulations of non-enteric capsules containingnon-enteric HCA that disintegrated in stomach fluids within 15-30 minand tablets usually within the same period of time and always withinless than 60 min.

Example 3 Slow-Release HCA Formulation

In one embodiment of the present invention, methacrylate polymer wasused as the film retardant. In the present example, Eudragit® was thepolymer used as a non pH-sensitive covering with the bioadhesives.

Eudragit® RS is available as a powder or a 30% aqueous dispersion. Thismethacrylate powder or solution is impermeable to water. Drugs entrappedin its matrix diffuse out by passive diffusion, regardless of the pH. Ithad a sticky component in pharmaceutical mixtures and therefore requiredthe use of ancillary agents, such as triethyl citrate, talc, and/ormagnesium stearate.

An example of this formulation in the use of slow release of HCA wasprepared according to the following composition (see Table 3):

TABLE 3 Amount Item # Ingredient (mg/Tablet) Percent 1 HCA potassiumsalt 750 76.14 2 Microcrystalline cellulose 20 2.03 3 Dicalciumphosphate 87 8.83 4 Corn Starch 9 0.91 5 TPGS 35 3.55 6 Hydrogenatedvegetable oil 35 3.55 7 Eudragit ® 30% RS 15 1.52 8 Triethyl citrate 50.51 9 Talc 10 1.02 10 Carbopol ® 974P carbomer 16 1.62 11 Magnesiumstearate 3 0.30 TOTAL 985 99.98

The method of preparation was as follows:

-   1. The potassium HCA salt was thoroughly dried before use and the    environment for preparation was low humidity. In a fluid bed dryer    screen items #1-5 were mixed and blended by blending agitation with    no heat.-   2. The material was then blended and sprayed with a mixture of talc,    triethyl citrate and Eudragit® 30% at 50 mL/kg of Eudragit® 37° C.    The temperature was not allowed to rise above 37° C. The blending    was continued with dry air until the LOD was <1.20%.-   3. The granulate was screened through a 093 D3 Fitzmill screen and    then blended with dry air in the fluid bed dryer. The Carbopol® 974    was added and agitated for 3 min or until fully blended with the    granulate.-   4. Next, the magnesium stearate was added to the granulate and    blended in a similar fashion until dry and free flowing.-   5. The dried granulate was then removed and placed on a rotary press    with oblong punches. The granulate was compressed into tablets    weighing 950 mg and having a fracture force strength of 12-15 kg.

Example 4

In another embodiment, predominately natural excipients were used toprolong the release of the HCA from the tablet matrix. In thisformulation, polyvinyl acetate was used as the retardant pH sensitivereleasing polymer. All other excipients were common USP ingredients. Aformulation of the following composition (see Table 4) was prepared:

TABLE 4 Amount Item # Ingredient (mg/Tablet) Percent 1 HCApotassium/magnesium salt 1,000 66.70 2 Di-calcium phosphate 174 11.60 3TPGS 40 2.60 4 Zein 21 1.40 5 Alginate (Satialgine) 49.5 3.30 6 Pectin60 4.00 7 Glycerin 100.5 6.70 8 Polyvinyl acetate phthalate (PVAP) 453.00 9 Magnesium stearate 10 0.70 TOTAL 1,500 100

The method of preparation was as follows:

-   1. HCA and di-calcium phosphate were blended in a fluid bed dryer.    When the HCA and di-calcium phosphate were blended, the TPGS was    melted under heat until it was free-flowing and molten. The molten    TPGS was then sprayed into the mixture of HCA and di-calcium    phosphate. The TPGS-containing mixture was further blended in fluid    bed dryer until a hard granulate formed.-   2. Zein was dissolved in 250 mL of methanol alcohol (reagent grade)    until the zein was well-dispersed.-   3. The hardened mixture of step 1 was then granulated in a fluid bed    with the fluidized zein and methanol.-   4. While the zein and dry material were blended, pectin was    prepared. Pectin was prepared by suspending the pectin into glycerin    using a high shear mixer until the pectin was thoroughly blended and    smooth in texture. The blended pectin was then slowly sprayed into    the zein-coated HCA. The pectin-containing, zein-coated mixture was    blended continuously until an even distribution of the components    was achieved. The mixture was further blended until a distinct    granulate formed. Blending was continued until the granulate was dry    and well-formed.-   5. For the last step in the granulation, screened alginate was added    into the mixture. The blending was continued at 30° C. temperature    for 15 min after the screened alginate was added. The    alginate-containing granulate was blended until dry with a loss on    drying (LOD)<1.5%.-   6. The granulate was sized by passing the granulate material through    a #120 Fitzmill screen. The sized granulate was then replaced into    fluid bed dryer. PVAP was then sprayed onto the sized and dried    granulate at room temperature while the granulate was agitated. The    PVAP was prepared by dispersing it in 300 mL of purified water with    30 mL of NH₃OH. The entire lot of PVAP was sprayed onto the    granulate and the material kept in the fluid bed dryer until the LOD    was <1.2%.-   7. The granulate was removed and passed through a 093 Fitzmill    screen prior to blending it with magnesium stearate.-   8. The screened granulate was then placed on a rotary press and    compressed into oblong tablets weighing 1,500 mg and having a    fracture force strength of 12±4 kg.

Example 5

For the purposes of production, it was useful to have a standardizedenteric starting material which has been stabilized for handlingpurposes and which could then be modified as to its release rate throughthe addition of ingredients, changes in handling and other techniques.Table 5 gives one formula that adds 5% solids from the coating to thestarting HCA material. This means that a starting HCA salt yielding 65%HCA can be added to formulas as an enteric-coated granulate andcalculated as 60% HCA. Kollicoat® IR(polyvinylalcohol-polyethyleneglycol graft-copolymer) is aninstant-release coating useful to create an HCA granulate compositionfor further processing that does not immediately become gummy whensubjected to moisture and other challenges. Eastacryl® from Eastman is adispersion of CAP (cellulose acetate pthalate) used to provide asustained-release coating.

TABLE 5 Enteric Coating using 2% Kollicoat IR and 3% Eastacryl Item #Ingredient Wt (Kg) Percent 1 HCA potassium/magnesium salt (65% HCA)2.000 76.34 2 Kollicoat IR 0.040 1.53 3 Water 0.380 14.50 4 Eastacryl(30% solids) 0.2 7.63 (yielding dissolved CAP solids) (0.06) TOTAL 2.62100.00

The method of preparation was as follows:

-   1. Items #1-3 were weighed and blended in a fluid bed dryer with    Kollicoat® IR as follows: Kollicoat IR was dissolved in 400 ml    water. Roughly 15 ml of alcohol was added to aid in drying. Product    then was spray dried onto the HCA salt in a fluid bed dryer with a    temperature <50° C. until moisture content was approximately 2.5%.-   2. The material produced in step 1 next was coated with Eastacryl®    in a fluid bed dryer to give it enteric characteristics.-   3. Coating technique information for the spray dryer for the    Eastacryl was as follows:    -   Spray rate: 9%    -   Outlet: 25-33° C.    -   Inlet: 45-55° C.    -   Atomizer: 55 PSI    -   CFM: 200-400    -   Dried to: 45° C. outlet temperature; inlet less than 60° C.-   4. With the loss of added water, the resulting enteric granulate,    referred to as HCActive™ (60%) Enteric Granulation, yields 60% HCA    and was suitable for incorporation into specific formulations of the    present invention.

Example 6

The procedure in Example 5 yielded a relatively durable granulate. Forsome purposes, an adequate enteric powder can be produced utilizingmagnesium stearate or similar compounds. Such a procedure requires lessequipment and less time.

TABLE 6 Enteric Coating using 5% Magnesium Stearate Item # Ingredient Wt(Kg) Percent 1 HCA potassium/magnesium salt (65% HCA) 2.000 95.24 2Magnesium Stearate 0.100 4.76 TOTAL 2.10 100.00

The method of preparation was as follows:

-   1. Items #1 and 2 were weighed and blended thoroughly.-   2. The material produced in step 1 next was heated to approximately    35° C. while blending continued. This step was continued long enough    to melt the magnesium stearate and coat the HCA salt evenly.-   3. Blending was maintained until the granulate had cooled to    approximately room temperature.-   4. The resulting granulate was screened through a 093 D3 Fitzmill    screen to control the size of the particles. The HCA content of the    resulting granulate was approximately 60%.

Example 7

In another embodiment, the HCActive™ (60%) Enteric Granulation producedin Example 5 was used to create an extended-release enteric formulationthat included TPGS. Additional delivery control came from the inclusionof Kollicoat® SR (polyvinylacetate dispersion stabilized with povidoneand sodium laurylsulfate). Kollicoat® SR provided a sustained-releasecoating.

TABLE 7 Extended Release (with Enteric and TPGS) Item Amount Wt Item #Key Ingredient (mg/Tablet) (Kg) Percent 1 Premix HCActive ™ (60%) 833.331.000 57.391 Enteric Granulation 2 TPGS 167 0.200 11.501 3 Kollicoat SR12.5 0.015 0.861 4 Silicon dioxide 167 0.200 11.501 (4% Aerosil) 5Starch 15 0.018 1.033 6 Mag Stearate 7 0.0234 0.502 7 Di-calcium 2500.300 17.219 Phosphate TOTAL 1451.83 1.7564 100.008

The method of preparation was as follows:

-   1. The Premix HCActive™ (60%) Enteric Granulation was produced as    indicated in Example 5.-   2. The molten TPGS was mixed with the Aerosil and then the product    was mixed with the Premix before being added to the other    ingredients and blended to achieve uniformity.-   3. The resulting granulate was screened through a 093 D3 Fitzmill    screen to control the size of the particles.-   4. The powder was then removed and placed on a rotary press with    oblong punches. It formed tablets readily. The granulate was    compressed into tablets weighing approximately 1450 mg and having a    fracture force strength of 12-15 kg.

There was little or no breakdown of these extended-release entericformulation-containing tablets upon exposure with stirring to simulategastric fluid without pepsin (HCl solution, pH 1.2) for 60 min. Theseextended-release enteric formulation-containing tablets dissolvedcompletely in approximately 55 min when agitated in monophosphatebuffer, pH 6.8 (as described previously in Example 1).

Example 8

In another embodiment, the HCActive™ (60%) Enteric Granulation producedin Example 5 was used to create an extended-release enteric formulationthat included TPGS. Unlike Example 6, in this example the TPGS was notfirst mixed with Aerosil, but rather liquefied and added to the totalpowder as described below.

TABLE 8 Extended Release (with Enteric and TPGS) Item Item Amount Wt #Key Ingredient (mg/Tablet) (Kg) Percent 1 Premix HCActive ™ (60%) 833.331.000 57.391 Enteric Granulation 2 TPGS 167 0.200 11.501 3 Kollicoat SR12.5 0.015 0.861 4 Microcrystalline 167 0.200 11.501 Cellulose 5 Starch15 0.018 1.033 6 Magnesium Stearate 7 0.0234 0.502 7 Di-calciumPhosphate 250 0.300 17.219 TOTAL 1451.83 1.7564 100.008

The method of preparation was as follows:

-   1. The Premix HCActive™ (60%) Enteric Granulation was produced as    indicated in Example 5.-   2. Molten TPGS was added to the Premix while mechanical blending was    taking place. The resultant mixture was an oily powder, improved for    handling by the addition of microcrystalline cellulose, followed by    the addition and blending of items #1, 3, 5, 6 into the whole.-   3. The resulting granulate was screened through a 093 D3 Fitzmill    screen to control the size of the particles.-   4. The powder was then removed and placed on a rotary press with    oblong punches. The granulate was compressed into tablets weighing    approximately 1450 mg. However, the tablets were brittle and of    uneven density.

These extended-release enteric formulation-containing tablets dissolvedcompletely in approximately 55 min when agitated in monophosphatebuffer, pH 6.8 (as described previously in Example 1).

Example 9

In another embodiment, the HCActive™ (60%) Enteric Granulation producedin Example 5 was used to create an extended-release enteric formulationthat included TPGS. Unlike Example 6, in this example the TPGS was firstmixed with a smaller amount of Aerosil and then refrigerated overnightto improve handling.

TABLE 9 Extended Release (Enteric with TPGS and Aerosil) Item ItemAmount Wt # Key Ingredient (mg/Tablet) (Kg) Percent 1 Premix HCActive ™(60%) 833.33 1.000 0.57339 Enteric Granulation 2 TPGS 167 0.200 0.114913 Aerosil 61 0.073 0.04197 4 Magnesium Stearate 7 0.0086 0.00482 5Di-calcium Phosphate 385 0.462 0.26491 TOTAL 1453.33 1.7436 1.00000

The method of preparation was as follows:

-   1. The Premix HCActive™ (60%) Enteric Granulation was produced as    indicated in Example 5.-   2. The TPGS was heated on a hot plate in stainless steel container    and then added to the Aerosil and mixed with a Kitchen Aide blender    to form a solid mass, then refrigerated overnight.-   2. The next day, TPGS/Aerosil block was broken up and reduced to    granulate, then this granulate was blended into the other    ingredients.-   3. The resulting material was screened through a 093 D3 Fitzmill    screen to control the size of the particles.-   4. The powder was then removed and placed on a rotary press with    oblong punches. The granulate was compressed into tablets weighing    approximately 1450 mg and having a fracture force strength of 12-15    kg.

These extended-release enteric formulation-containing tablets dissolvedcompletely in approximately 45 min when agitated in monophosphatebuffer, pH 6.8 (as described previously in Example 1).

Example 10

In another embodiment, the HCActive™ (60%) Enteric Granulation producedin Example 5 was used to create an extended release enteric formulationthat included Lubritab® in place of TPGS. Lubritab® could be mixed intothe formulation as a dry powder and did not require the extensivepretreatment that TPGS needed.

TABLE 10 Extended Release (Enteric with Lubritab) Item Item Amount Wt #Key Ingredient (mg/Tablet) (Kg) Percent 1 Premix HCA (60%) Enteric833.33 1.000 55.543 Granulation 2 Di-calcium Phosphate 332 0.376 22.1283 Lubritab 228 0.258 15.197 4 Kollicoat SR 100 0.113 6.665 5 MagnesiumStearate 7 0.0082 0.466 TOTAL 1500.33 1.7552 99.999

The method of preparation was as follows:

-   1. The Premix HCActive™ (60%) Enteric Granulation was produced as    indicated in Example 5.-   2. All ingredients were blended together.-   3. The resulting material was screened through a 093 D3 Fitzmill    screen to control the size of the particles.-   4. The powder was then removed and placed on a rotary press with    oblong punches. The granulate was compressed into tablets weighing    approximately 1500 mg and having a fracture force strength of 12-15    kg.

These extended-release enteric formulation-containing tablets took morethan 12 h to dissolved completely when agitated in monophosphate buffer,pH 6.8 (as described previously in Example 1). The wicking action ofAerosil, microcrystalline cellulose or some similar component is usefulto augment this enteric formulation in order to decrease the dissolutiontime. Using the formulations of the invention, HCA release rates couldbe controlled for periods of at least about 30 min to more than about 12h at pH 6.8. Lubritab® was a useful substitute for TPGS in theHCA-containing compounds of the present invention.

Example 11 Comparative Analysis of the Chloride Content and TotalHalogen Content of HCA-Containing Compound of the Present Invention andAnother Commercial HCA-Containing Preparation

The chloride content of select HCA-containing preparations wasdetermined by elemental and ion chromatographic analysis by GalbraithLaboratories, Inc. (Knoxyille, Tenn.) as summarized in Tables 11 and 12below. As shown in Table 11, the chloride content of an HCA-containingcompound of the present invention (RH1-1) was at least 6-fold lower thanthe chloride content of a commercial HCA-containing preparation (SCM-1)according to ion exchange chromatography employing standard techniquessatisfying Environmental Protection Agency (EPA) methods/EPA 300.0.

TABLE 11 Chloride Content Weight Percent Sample ID Test Sample 1 TestSample 2 RH1-1 0.427 0.424 SCM-1 2.71 2.65

Chloride content is tightly controlled in many countries for healthreasons. The HCA-containing compound was produced using the methodspreviously described in U.S. Pat. Nos. 5,656,314 and 5,536,516 and thenfurther processed as follows. Briefly, a solution of HCA-containingcompound was passed over a small volume of strong anion exchange columnwhere preferentially chlorides are bound along with HCA. Minimum amountof HCA is lost but the chlorides are reduced considerably so as toachieve chloride levels of less than about 0.6%. Afterward, thissolution is treated with charcoal and reacted with magnesium andpotassium according to our art, to get a Mg—K HCA which is subsequentlyspray-dried to derive less hygroscopic free-flowing powder. In oneembodiment of the present invention, elemental magnesium and elementalpotassium are present in the HCA-containing compound in a ratio ofbetween about 1:10 to about 1:3.

Halogen refers to those elements in the seventeenth column of theperiodic table: fluorine (F), chlorine (Cl), bromine (Br), iodine (I),and astatine (At). Halogenated refers to a chemical compound or mixturethat contains halogen atoms. In a covalent molecule, the halide atom hasa strong, directional chemical bond to another atom. If this other atomis a carbon atom the material is a halogenated organic molecule, e.g.,carbon tetrachloride, methylene chloride (dichloromethane),trichloroethylene, polyvinyl chloride (PVC). Halogenated organicmolecules are a very important class of chemicals that are used toproduce a wide variety of other chemicals and consumer products. When acovalent halide dissolves, the halogen atom remains firmly attached towhatever it was bonded to and is not an electrolyte. Chlorinated organicmolecules are often health hazards and some are even known humancarcinogens. Generally, the more chlorine atoms an organic molecule has,the more likely it is to be carcinogenic. Accordingly, the totalhalogens as chloride content of select HCA-containing preparations wasdetermined by Galbraith Laboratories, Inc. (Knoxyille, Tenn.) assummarized in Table 12 below.

Total elemental chlorine was determined using the EnvironmentalProtection Agency (EPA) method/EPA 330.5 (yielding total residualchlorine). Elemental analysis is superior to ion analysis in cases inwhich chlorine is molecularly bound such as to not be readily releasedthrough oxidation or other techniques and in certain other instances.The findings for both samples with elemental analysis were slightlyhigher than those with ion determination. As shown in Table 12, thetotal halogens as chloride content of an HCA-containing compound of thepresent invention (RH1-1) was at least 5-fold lower than the totalhalogens as chloride content of a commercial HCA-containing preparation(SCM-1).

TABLE 12 Total Halogens as Chloride Content Weight Percent Sample IDTest Sample 1 Test Sample 2 RH1-1 0.603 0.599 SCM-1 3.02 3.05

Example 12 Testing the HCA-Containing Compounds in a Rat Model

An OM rat model is useful to test the biological properties of theHCA-containing compounds of the invention. Briefly, male OM rats aged 10weeks are fed a diet in which 30% of the calories are obtained from fatunder standard conditions. Groups of 5-10 rats are intubated twice dailywith HCA-containing test compound (e.g., 0.01 mmoles/kg body weight to 1mole/kg body weight) or placebo for 60 days. Blood is withdrawn from thetail vein one or more times daily. The pharmacokinetics ofHCA-containing compounds, including absorption, is determined bymeasuring the HCA level in the blood of subjects administered theHCA-containing compound using gas chromatography/mass spectroscopytechnique (Loe et al., Anal Biochem. 2001, 1; 292(1): 148-54) and asfurther detailed by Loe et al., (FASEB Journal, 2001, 15 4:632, Abs.501.1). Body weight of the test subjects as well as, blood levels oflipids, hormones and metabolic regulators are measured, e.g., but notlimited to, LDL and HDL, glucocorticoids, leptin, insulin, andcorticosterone level (see generally, U.S. Pat. No. 6,482,858, issuedNov. 19, 2002). At the end of the 60 day experimental period, theanimals are sacrificed. Experimental parameters such as body weight ofthe test subjects as well as, blood levels of lipids, hormones andmetabolic regulators are measured, e.g., but not limited to, LDL andHDL, glucocorticoids, leptin, insulin, and corticosterone level in testsubjects receiving HCA-containing compound is compared with theseexperimental parameters in subjects receiving placebo by statisticalanalysis using the Students t-test (one- or two-tailed P-values) orANOVA. A P-value of less than or equal to about 0.05 is consideredstatistically significant. A statistically significant alteration, e.g.,increase or decrease, in an experimental parameter of test subjectsreceiving HCA-containing compound compared to subjects receiving placeboindicates that the HCA-containing compound is a drug capable of theprevention or treatment of diseases or conditions characterized byalterations in such parameters.

EQUIVALENTS

From the foregoing detailed description of the invention, it should beapparent that unique HCA-containing compounds and methods of the samehave been described resulting in improved HCA-containing formulationssuitable for therapeutic use. Although particular embodiments have beendisclosed herein in detail, this has been done by way of example forpurposes of illustration only, and is not intended to be limiting withrespect to the scope of the appended claims which follow. In particular,it is contemplated by the inventor that substitutions, alterations, andmodifications may be made to the invention without departing from thespirit and scope of the invention as defined by the claims. Forinstance, the choice of HCA salt, encapsulating agent or the choice ofappropriate patient therapy based on these is believed to be matter ofroutine for a person of ordinary skill in the art with knowledge of theembodiments described herein.

1. A (−)-hydroxycitrate-containing composition, comprising: (a)(−)-hydroxycitrate; (b) one or moreabsorption-enhancer/controlled-release agents; and (c) one or morerate-controlling excipients. 2-188. (canceled)